Kaletra Drug Information

is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 14 days and older. Limitations of Use: Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA . KALETRA is an HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The safety of KALETRA has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.

In clinical studies the incidence of diarrhea in patients treated with either KALETRA capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.

Commonly reported adverse reactions to KALETRA included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 8): Table 8. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving KALETRA in Combined Phase II/IV Studies (N=2,612) System Organ Class (SOC) and Adverse Reaction n % BLOOD AND LYMPHATIC SYSTEM DISORDERS anemia* 54 2.1 leukopenia and neutropenia* 44 1.7 lymphadenopathy* 35

CARDIAC

DISORDERS atherosclerosis such as myocardial infarction* 10 0.4 atrioventricular block* 3 0.1 tricuspid valve incompetence* 3

EAR

AND LABYRINTH DISORDERS vertigo* 7 0.3 tinnitus 6

ENDOCRINE

DISORDERS hypogonadism* 16 0.8 1 EYE DISORDERS visual impairment* 8

GASTROINTESTINAL

DISORDERS diarrhea* 510 19.5 nausea 269 10.3 vomiting* 177 6.8 abdominal pain (upper and lower)* 160 6.1 gastroenteritis and colitis* 66 2.5 dyspepsia 53 2.0 pancreatitis* 45

Gastroesophageal Reflux Disease (GERD)* 40 1.5 hemorrhoids 39 1.5 flatulence 36 1.4

abdominal distension 34 1.3 constipation* 26 1.0 stomatitis and oral ulcers* 24 0.9 duodenitis and gastritis* 20 0.8 gastrointestinal hemorrhage including rectal hemorrhage* 13 0.5 dry mouth 9 0.3 gastrointestinal ulcer* 6 0.2 fecal incontinence 5

GENERAL

DISORDERS AND ADMINISTRATION SITE CONDITIONS fatigue including asthenia* 198

HEPATOBILIARY

DISORDERS hepatitis including AST, ALT, and GGT increases* 91 3.5 hepatomegaly 5 0.2 cholangitis 3 0.1 hepatic steatosis 3

IMMUNE

SYSTEM DISORDERS hypersensitivity including urticaria and angioedema* 70 2.7 immune reconstitution syndrome 3

INFECTIONS

AND INFESTATIONS upper respiratory tract infection* 363 13.9 lower respiratory tract infection* 202 7.7 skin infections including cellulitis, folliculitis, and furuncle* 86

METABOLISM

AND NUTRITION DISORDERS hypercholesterolemia* 192 7.4 hypertriglyceridemia* 161 6.2 weight decreased* 61 2.3 decreased appetite 52 2.0 blood glucose disorders including diabetes mellitus* 30 1.1 weight increased* 20 0.8 lactic acidosis* 11 0.4 increased appetite 5

MUSCULOSKELETAL

AND CONNECTIVE TISSUE DISORDERS musculoskeletal pain including arthralgia and back pain* 166 6.4 myalgia* 46 1.8 muscle disorders such as weakness and spasms* 34 1.3 rhabdomyolysis* 18 0.7 osteonecrosis 3

NERVOUS

SYSTEM DISORDERS headache including migraine* 165 6.3 insomnia* 99 3.8 neuropathy and peripheral neuropathy* 51 2.0 dizziness* 45 1.7 ageusia* 19 0.7 convulsion* 9 0.3 tremor* 9 0.3 cerebral vascular event* 6

PSYCHIATRIC

DISORDERS anxiety* 101 3.9 abnormal dreams* 19 0.7 libido decreased 19

RENAL

AND URINARY DISORDERS renal failure* 31 1.2 hematuria* 20 0.8 nephritis* 3

REPRODUCTIVE

SYSTEM AND BREAST DISORDERS erectile dysfunction* 34 1.7 1 menstrual disorders - amenorrhea, menorrhagia* 10 1.7 2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS rash including maculopapular rash* 99 3.8 lipodystrophy acquired including facial wasting* 58 2.2 dermatitis/rash including eczema and seborrheic dermatitis* 50 1.9 night sweats* 42 1.6 pruritus* 29 1.1 alopecia 10 0.4 capillaritis and vasculitis* 3

VASCULAR

DISORDERS hypertension* 47 1.8 deep vein thrombosis* 17 0.7 *Represents a medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574) Laboratory Abnormalities in Adults The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 9 (treatment-naïve patients) and Table 10 (treatment-experienced patients). Table 9. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients Study 863 (48 Weeks) Study 720 (360 Weeks) Study 730 (48 Weeks) Variable Limit 1 KALETRA 400/100 mg Twice Daily + d4T +3TC (N = 326) Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) KALETRA Twice Daily + d4T + 3TC (N = 100) KALETRA Once Daily + TDF +FTC (N=333) KALETRA Twice Daily + TDF +FTC (N=331) Chemistry High Glucose > 250 mg/dL 2% 2% 4% 0% <1% Uric Acid > 12 mg/dL 2% 2% 5% <1% 1% SGOT/ AST 2 > 180 U/L 2% 4% 10% 1% 2% SGPT/ ALT 2 >215 U/L 4% 4% 11% 1% 1% GGT >300 U/L N/A N/A 10% N/A N/A Total Cholesterol >300 mg/dL 9% 5% 27% 4% 3% Triglycerides >750 mg/dL 9% 1% 29% 3% 6% Amylase >2 x ULN 3% 2% 4% N/A N/A Lipase >2 x ULN N/A N/A N/A 3% 5% Chemistry Low Calculated Creatinine Clearance <50 mL/min N/A N/A N/A 2% 2% Hematology Low Neutrophils <0.75 x 10 9 /L 1% 3% 5% 2% 1% 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Criterion for Study 730 was >5x ULN (AST/ALT). Table 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients Study 888 (48 Weeks) Study 957 2 and Study 765 3 (84-144 Weeks) Study 802 (48 Weeks) Variable Limit 1 KALETRA 400/100 mg Twice Daily + NVP + NRTIs (N = 148) Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140) KALETRA Twice Daily + NNRTI + NRTIs (N = 127) KALETRA 800/200 mg Once Daily +NRTIs (N=300) KALETRA 400/100 mg Twice Daily +NRTIs (N=299) Chemistry High Glucose >250 mg/dL 1% 2% 5% 2% 2% Total Bilirubin >3.48 mg/dL 1% 3% 1% 1% 1% SGOT/AST 4 >180 U/L 5% 11% 8% 3% 2% SGPT/ALT 4 >215 U/L 6% 13% 10% 2% 2% GGT >300 U/L N/A N/A 29% N/A N/A Total Cholesterol >300 mg/dL 20% 21% 39% 6% 7% Triglycerides >750 mg/dL 25% 21% 36% 5% 6% Amylase >2 x ULN 4% 8% 8% 4% 4% Lipase >2 x ULN N/A N/A N/A 4% 1% Creatine Phosphokinase >4 x ULN N/A N/A N/A 4% 5% Chemistry Low Calculated Creatinine Clearance <50 mL/min N/A N/A N/A 3% 3% Inorganic Phosphorus <1.5 mg/dL 1% 0% 2% 1% <1% Hematology Low Neutrophils <0.75 x 10 9 /L 1% 2% 4% 3% 4% Hemoglobin <80 g/L 1% 1% 1% 1% 2% 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received KALETRA in combination with NRTIs and efavirenz. 3 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 36) or 400/200 mg twice daily (n = 34) for 144 weeks. Patients received KALETRA in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was >5x ULN (AST/ALT). Adverse Reactions in Pediatric Patients KALETRA oral solution dosed up to 300/75 mg/m 2 has been studied in 100 pediatric patients 6 months to 12 years of age.

The adverse reaction profile seen during Study 940 was similar to that for adult patients. Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia.

Rash was the only event of those listed that occurred in 2 or more subjects (N = 3). KALETRA oral solution dosed at 300/75 mg/m 2 has been studied in 31 pediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects.

Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2). KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m 2 (without concomitant NNRTI) and 480/120 mg/m 2 (with concomitant NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities. Laboratory Abnormalities in Pediatric Patients The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 11. Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940 Variable Limit 1 KALETRA Twice Daily + RTIs (N = 100) Chemistry High Sodium > 149 mEq/L 3% Total Bilirubin ≥ 3.0 x ULN 3% SGOT/AST > 180 U/L 8% SGPT/ALT > 215 U/L 7% Total Cholesterol > 300 mg/dL 3% Amylase > 2.5 x ULN 7% 2 Chemistry Low Sodium < 130 mEq/L 3% Hematology Low Platelet Count < 50 x 10 9 /L 4% Neutrophils < 0.40 x 10 9 /L 2% 1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of KALETRA. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to KALETRA exposure. Body as a Whole Redistribution/accumulation of body fat has been reported . Cardiovascular Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes . Renal and Urinary Disorders Nephrolithiasis Skin and Appendages Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.

• Co-administration of KALETRA can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. The potential for drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for KALETRA to Affect Other Drugs Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 12. Additionally, KALETRA induces glucuronidation. Published data suggest that lopinavir is an inhibitor of OATP1B1. These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information. 7.2 Potential for Other Drugs to Affect Lopinavir Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. 7.3 Established and Other Potentially Significant Drug Interactions Table 12 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] for magnitude of interaction. Table 12. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments HIV-1 Antiviral Agents HIV-1 Protease Inhibitor: fosamprenavir/ritonavir ↓ amprenavir ↓ lopinavir An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV-1 Protease Inhibitor: indinavir* ↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir. HIV-1 Protease Inhibitor: nelfinavir* ↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration ( 2 )] . HIV-1 Protease Inhibitor: ritonavir* ↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. HIV-1 Protease Inhibitor: tipranavir* ↓ lopinavir Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended. HIV CCR5 – Antagonist: maraviroc* ↑ maraviroc When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc. Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* ↓ lopinavir Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration ( 2 )] . Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established. Nucleoside Reverse Transcriptase Inhibitor: didanosine KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate* ↑ tenofovir Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine ↓ abacavir ↓ zidovudine The clinical significance of this potential interaction is unknown. Other Agents Alpha 1- Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications ( 4 )] . Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications ( 4 )] . Antiarrhythmics: dronedarone ↑ dronedarone Contraindicated due to potential for cardiac arrhythmias [see Contraindications ( 4 )] . Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. Anticancer Agents: abemaciclib, apalutamide, encorafenib, ibrutinib, ivosidenib, dasatinib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓lopinavir/ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors [see Contraindications ( 4 )] . Avoid co-administration of encorafenib or ivosidenib with KALETRA due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with KALETRA cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with KALETRA cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with KALETRA. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Anticoagulants: warfarin, rivaroxaban ↑↓ warfarin ↑ rivaroxaban Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding. Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ lopinavir ↓ phenytoin KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. Anticonvulsants: lamotrigine, valproate ↓ lamotrigine ↓ or ↔ valproate A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. Antidepressant: bupropion ↓ bupropion ↓ active metabolite, hydroxybupropion Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. Antidepressant: trazodone ↑ trazodone Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. Antifungals: ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate* ↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients. Anti-gout: colchicine ↑ colchicine Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications ( 4 )] . For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifampin ↓ lopinavir Contraindicated due to potential loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents [see Contraindications ( 4 )] . Antimycobacterial: bedaquiline ↑ bedaquiline Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk. Antimycobacterial: rifabutin* ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed. Antipsychotics: lurasidone pimozide ↑ lurasidone ↑ pimozide Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications ( 4 )] . Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications ( 4 )] . Antipsychotics: quetiapine ↑ quetiapine Initiation of KALETRA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking KALETRA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Contraceptive: ethinyl estradiol* ↓ ethinyl estradiol Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine ↑ dihydropyridine calcium channel blockers Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered. Disulfiram/metronidazole KALETRA oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). Endothelin Receptor Antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications ( 4 )] . GI Motility Agent: cisapride ↑ cisapride Contraindicated due to potential for cardiac arrhythmias [see Contraindications ( 4 )] . GnRH Receptor Antagonists: elagolix ↑ elagolix ↓ lopinavir/ritonavir Concomitant use of elagolix 200 mg twice daily and KALETRA for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and KALETRA to 6 months. Hepatitis C direct acting antiviral: elbasvir/grazoprevir ↑ elbasvir/grazoprevir Contraindicated due to increased risk of alanine transaminase (ALT) elevations [see Contraindications ( 4 )] . Hepatitis C direct acting antivirals: boceprevir* glecaprevir/pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilaprevir ombitasvir/paritaprevir/ ritonavir and dasabuvir* ↓ lopinavir ↓ boceprevir ↓ ritonavir ↑glecaprevir ↑ pibrentasvir ↑ simeprevir ↑ sofosbuvir ↑ velpatasvir ↑ voxilaprevir ↑ ombitasvir ↑ paritaprevir ↑ ritonavir ↔ dasabuvir It is not recommended to co-administer KALETRA and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir. Herbal Products: St. John's Wort (hypericum perforatum) ↓ lopinavir Contraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors [see Contraindications ( 4 )] . Lipid-modifying agents HMG-CoA Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 )] . Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications ( 4 )] . Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. Kinase Inhibitors: fostamatinib (also see anticancer agents above) ↑ fostamatinib metabolite R406 Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Long-acting beta-adrenoceptor Agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Narcotic Analgesics: methadone,* fentanyl ↓ methadone ↑ fentanyl Dosage of methadone may need to be increased when co-administered with KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio ® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications ( 4 )] . Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ® ) is contraindicated [see Contraindications ( 4 )] . The following dose adjustments are recommended for use of tadalafil (Adcirca ® ) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses:
• Sildenafil: 25 mg every 48 hours
• Tadalafil: 10 mg every 72 hours
• Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications ( 4 )] . Sedative/Hypnotics: parenterally administered midazolam ↑ midazolam If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↓ lopinavir ↑ glucocorticoids Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. * see Clinical Pharmacology ( 12.3 ) for magnitude of interaction. # refers to interaction with apalutamide. 7.4 Drugs with No Observed or Predicted Interactions with KALETRA Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine. Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group.

The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses. Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions . There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period.

Once daily KALETRA dosing is not recommended in pregnancy. Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%. Data Human Data KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial . No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.

Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens.

For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. Animal Data Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a pre- and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.

No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

Pediatric Use The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be administered once daily in pediatric patients. An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m 2 twice daily plus two NRTIs in HIV-infected infants ≥14 days and < 6 months of age.

Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC 12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-1 RNA <400 copies/mL at Week 24 . Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years. Dose selection for patients 6 months to 12 years of age was based on the following results.

The 230/57.5 mg/m 2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m 2 oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine) . A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m 2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m 2 twice daily + ≥ 1 NRTI + 1 NNRTI) in 26 children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance.

High doses of KALETRA exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks . A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of KALETRA tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged < 18 years, ≥ 15 kg in weight, receiving cART that included KALETRA, HIV-1 ribonucleic acid (RNA) < 50 copies/mL for at least 24 weeks and able to swallow tablets. At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing. The safety profile was similar between the two treatment arms although there was a greater incidence of diarrhea in the once daily treated subjects.

is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir. KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions . ○ Alpha 1- Adrenoreceptor Antagonist: alfuzosin ○ Antianginal: ranolazine ○ Antiarrhythmic: dronedarone ○ Anti-gout: colchicine ○ Antipsychotics: lurasidone, pimozide ○ Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ○ GI Motility Agent: cisapride ○ Hepatitis C direct acting antiviral: elbasvir/grazoprevir ○ HMG-CoA Reductase Inhibitors: lovastatin, simvastatin ○ Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ○ PDE5 Inhibitor: sildenafil (Revatio ® ) when used for the treatment of pulmonary arterial hypertension ○ Sedative/Hypnotics: triazolam, orally administered midazolam KALETRA is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance . ○ Anticancer Agents: apalutamide ○ Antimycobacterial: rifampin ○ Herbal Products: St. John's Wort (hypericum perforatum) Hypersensitivity to KALETRA (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir.

Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. Co-administration with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross resistance.

Overdoses with KALETRA oral solution have been reported. One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of KALETRA oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure . Healthcare professionals should be aware that KALETRA oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose.

This is especially important for infants and young children. KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Ingestion of the product over the recommended dose by an infant or a young child could result in significant toxicity and could potentially be lethal.

Human experience of acute overdosage with KALETRA is limited. Treatment of overdose with KALETRA should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with KALETRA. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage.

Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with KALETRA oral solution.